A. Idiopathic or Familial

Most women with hirsutism or androgenic alopecia have no detectable hyperandrogenism; hirsutism may be considered normal in the context of their genetic background. Such patients may have elevated serum levels of androstenediol glucuronide, a metabolite of dihydrotestosterone that is produced by skin in cosmetically unacceptable amounts.

B. Polycystic Ovary Syndrome (Hyperthecosis, Stein-Leventhal Syndrome)

PCOS is a common functional disorder of the ovaries of unknown etiology (see Chapter 20). It accounts for at least 50% of all cases of hirsutism associated with elevated serum testosterone levels. It is familial and transmitted as a complex polygenic disorder whose phenotypic expression may involve both protective and susceptible genomic variants.

A diagnosis of PCOS must meet three criteria: (1) androgen excess with clinical hyperandrogenism or elevated serum free or total testosterone; (2) ovarian dysfunction with oligoanovulation or polycystic ovary morphology; and (3) absence of other causes of testosterone excess or anovulation such as pregnancy, thyroid dysfunction, 21-hydroxylase deficiency, neoplastic testosterone secretion, Cushing syndrome, or hyperprolactinemia.

Affected women usually have signs of hyperandrogenism, including hirsutism, acne, or male-pattern thinning of scalp hair; this persists after natural menopause. However, women of East Asian descent are less likely to exhibit hirsutism. Most women also have elevated serum testosterone or free testosterone levels. About 70% of affected women have polycystic ovaries on pelvic ultrasound and 50% have oligomenorrhea or amenorrhea with anovulation. Of note, about 30% of women with PCOS do not have cystic ovaries and 25-30% of normal menstruating women have cystic ovaries.

Obesity and high serum insulin levels (due to insulin resistance) contribute to the syndrome in 70% of women. The serum LH:FSH ratio is often greater than 2.0. Both adrenal and ovarian androgen hypersecretion are commonly present. Women with PCOS have a 35% risk of depression, compared with 11% in age-matched controls. Diabetes mellitus is present in about 13% of cases. Obstructive sleep apnea is particularly common, even in slender women with PCOS. Untreated women with amenorrhea have a slightly increased risk of endometrial carcinoma. Hypertension and hyperlipidemia are often present, increasing the risk of CVD. Women frequently regain normal menstrual cycles with aging.

C. 46,XX Karyotype: Congenital Adrenal Hyperplasia

Congenital adrenal steroidogenic enzyme defects result in reduced cortisol secretion with a compensatory increase in ACTH that causes adrenal hyperplasia. The most common enzyme defect in 46,XX is 21-hydroxylase deficiency, with a prevalence of about 1:18,000. Girls with severe "classic" 21-hydroxylase deficiency present with ambiguous genitalia at birth and may become virilized unless treated with corticosteroid replacement. Boys are particularly prone to escape detection at birth and typically present later with shock and hyponatremia.

Congenital adrenal hyperplasia (CAH) can present at birth with clitoromegaly or later in puberty as hirsutism or virilization. Partial deficiency in adrenal 21-hydroxylase can present in women as hirsutism. About 2% of patients with adult-onset hirsutism have been found to have a partial defect in adrenal 21-hydroxylase. The condition is more common in Ashkenazi Jews, Yupic Alaskans, and natives of La Reunion Island. The phenotypic expression is delayed until adolescence or adulthood; such patients do not have salt wasting. Polycystic ovaries and adrenal adenomas are more likely to develop in these women.

Some rare patients with hyperandrogenism and hypertension have 11-hydroxylase deficiency. This is distinguished from cortisol resistance by high cortisol serum levels in the latter and by high serum 11-deoxycortisol levels in the former.

Patients with an XY karyotype and a deficiency in 17-beta-hydroxysteroid dehydrogenase-3 or a deficiency in 5-alpha-reductase-2 may present as phenotypic girls in whom virilization develops at puberty.

D. 46,Xy Karyotype: Defects in Androgen Action or Synthesis

Phenotypically normal-appearing girls with a 46,XY karyotype can virilize to various extent at puberty. This can be caused by partial androgen insensitivity syndrome. Virilization at puberty can also be caused by mutations in the SRD5A2 gene, resulting in 5-alpha-reductase deficiency that causes a reduced conversion of testosterone to dihydrotestosterone. Gonadal dysgenesis (GD) refers to incomplete differentiation of the gonads. It can be caused by several different germline mutations and can cause hirsutism or virilization at puberty.

E. Neoplastic Disorders

Ovarian tumors are uncommon causes of hirsutism (0.8%) and include arrhenoblastomas, Sertoli-Leydig cell tumors, dysgerminomas, and hilar cell tumors. Adrenal carcinoma, a rare cause of Cushing syndrome and hyperandrogenism, can be quite virilizing. Pure androgen-secreting adrenal tumors occur very rarely; about 50% are malignant.

F. Rare Causes of Hirsutism & Virilization

Acromegaly and ACTH-induced Cushing syndrome are rare causes of hirsutism and virilization. Porphyria cutanea tarda can cause periorbital hair growth in addition to dermatitis in sun-exposed areas. Maternal virilization during pregnancy may result from a luteoma of pregnancy, hyperreactio luteinalis, or polycystic ovaries. In postmenopausal women, diffuse stromal Leydig cell hyperplasia is a rare cause of hyperandrogenism. Acquired hypertrichosis lanuginosa, which is diffuse fine lanugo hair growth on the face and body along with stomatologic symptoms, is usually associated with an internal malignancy, especially colorectal cancer, and may regress after tumor removal. Pharmacologic causes include minoxidil, cyclosporine, phenytoin, anabolic steroids, interferon, cetuximab, diazoxide, and certain progestins.

A. Symptoms and Signs

Modest androgen excess from any source increases sexual hair (chin, upper lip, abdomen, and chest) and increases sebaceous gland activity, producing acne. Menstrual irregularities, anovulation, and amenorrhea are common. If androgen excess is pronounced, defeminization (decrease in breast size, loss of feminine adipose tissue) and virilization (frontal balding, muscularity, clitoromegaly, and deepening of the voice) occur. Virilization points to the presence of an androgen-producing neoplasm.

Hirsutism is quantitated using the Ferriman-Gallwey score; hirsutism is graded from 0 (none) to 4 (severe) in nine areas of the body (maximum possible score is 36) (http://education.endocrine.org/ferriman-gallwey-hirsutism-system). Scores below 8 are considered mild hirsutism and normal variants. Scores of 8-15 indicate moderate hirsutism. Scores over 15 indicate severe hirsutism. Of note, the normal score is lower in Asian women and higher in Mediterranean women.

A pelvic examination may disclose clitoromegaly or ovarian enlargement that may be cystic or neoplastic. Hypertension may be present in Cushing syndrome, adrenal 11-hydroxylase deficiency, or cortisol resistance syndrome.

B. Laboratory Testing and Imaging

Serum androgen testing is mainly useful to screen for rare occult adrenal or ovarian neoplasms. Testing is warranted for women with moderate to severe hirsutism, mild hirsutism with menstrual disturbances, and women with worsening hirsutism despite therapy. Some general guidelines are presented here, though exceptions are common.

Serum is assayed for total testosterone and free testosterone. A serum testosterone level greater than 200 ng/dL (6.9 nmol/L) or free testosterone greater than 40 ng/dL (140 pmol/L) indicates the need for a manual pelvic examination and pelvic ultrasound. If that is negative, an adrenal CT scan is performed. A serum androstenedione level greater than 1000 ng/dL (34.9 nmol/L) also points to an ovarian or adrenal neoplasm.

Patients with a serum DHEAS greater than 700 mcg/dL (35 nmol/L) have an adrenal source of androgen. This usually is due to adrenal hyperplasia and rarely to adrenal carcinoma. Patients with any clinical signs of Cushing syndrome should receive a screening test (eg, 1-mg overnight dexamethasone suppression test) (see Cushing Syndrome, above).

Screening for nonclassical "late-onset" congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is warranted for women with (1) high serum testosterone or free testosterone levels and (2) hirsutism with normal serum testosterone levels who are at high risk for CAH due to having a family history of hirsutism or being a member of a high-risk ethnic group (eg, Ashkenazi Jews, Croatians, Iranians, Yupik Inuit). The evaluation requires an early morning blood draw for serum 17-hydroxyprogesterone, ideally during the follicular (early) phase of the menstrual cycle or on a random day for women with irregular menses or amenorrhea. Patients with CAH usually have a baseline 17-hydroxyprogesterone level greater than 300 ng/dL (9.1 nmol/L). Serum levels of FSH and LH are elevated if amenorrhea is due to ovarian failure. An LH:FSH ratio greater than 2.0 is common in patients with PCOS. On abdominal ultrasound, about 25-30% of normal young women have polycystic ovaries, so the appearance of ovarian cysts on ultrasound is not helpful. Pelvic ultrasound or MRI usually detects virilizing tumors of the ovary. However, small virilizing ovarian tumors may not be detectable on imaging studies; selective venous sampling for testosterone may be used for diagnosis in such patients.

A. Laser and Topical Treatments

Local treatment of facial hirsutism is by shaving or depilatories, waxing, electrolysis, or bleaching. Eflornithine (Vaniqa) 13.9% topical cream retards hair growth when applied twice daily to unwanted facial hair; improvement is noted within 4-8 weeks. Eflornithine may be used during laser therapy for a more dramatic response. However, local skin irritation may occur. Hirsutism returns with discontinuation, unless it is given with laser therapy.

Laser therapy (photoepilation) can be a very effective treatment for facial hirsutism, particularly for women with dark hair and light skin. For women of color, a longer-wavelength laser such as Nd:YAG or diode laser given with skin cooling is used. In such women, laser removal of facial hair significantly improves hirsutism. Repeated laser treatments are usually required. However, laser does not remove nonpigmented hairs. Potential side effects include local pain, erythema, and hyperpigmentation (20%) that usually resolves; skin hypopigmentation occurs rarely. Accidental eye injuries have been reported; eye shields should be used during treatments. Laser therapy is not recommended for Middle Eastern and Mediterranean women with facial hirsutism, since they have a particularly increased risk of paradoxical hypertrichosis with laser therapy.

Topical minoxidil may be used to treat androgenic alopecia and is mildly effective when applied to the scalp twice daily. Only the 2% formulation is FDA-approved for women.

B. Medications

Oral contraceptives are warranted as an initial therapy for women with hirsutism who are not actively pursuing pregnancy. To reduce the risk of DVT, an oral contraceptive is recommended with a low-dose of estradiol (20 mcg) and a progestin having a relatively low risk of venous thrombosis (norethindrone, norgestimate, levonorgestrel). A favored formulation for daily use contains norethindrone 1 mg with ethinyl estradiol 20 mcg. Nevertheless, such oral contraceptives confer over twofold increased risk of DVT. Also, levonorgestrel causes insulin resistance, so its use is problematic in women with polycystic ovary syndrome. Oral contraceptives that contain particularly antiandrogenic progestins such as desogestrel (Azurette, Kariva), drospirenone (Yaz, Gianvi), norgestimate (Ortho Tri-Cyclen Lo), or cyproterone acetate (Diane 35, not available in United States) more effectively reduce hirsutism and acne; however, such antiandrogenic oral contraceptives confer a fourfold risk of DVT, and their use is discouraged in high-risk patients.

Cyproterone acetate is a unique progestin that is used to treat women with hirsutism worldwide, except in the United States, where it is not FDA-approved. Cyproterone acetate blocks androgen receptors as well as 5-alpha-reductase activity while also suppressing testosterone levels. It is typically prescribed as an oral contraceptive in a dose of 2 mg with ethinyl estradiol 35 mcg.

Combined oral contraceptives are relatively contraindicated for women who have a personal history of or who are predisposed to thromboembolism, such as women who (1) are smokers, (2) have migraines, (3) are over age 39 years, (4) have obesity, or (5) have hypertension. Metabolic syndrome and hypertriglyceridemia are seen, particularly with antiandrogenic progestins.

Spironolactone is effective for reducing hirsutism, acne, and androgenic alopecia in women. It may be taken in doses of 100-200 mg orally daily (taken as a single dose or in two divided doses) on days 5-25 of the menstrual cycle or daily if used concomitantly with an oral contraceptive. Spironolactone is contraindicated in pregnancy, so reproductive-age women must use reliable contraception during this therapy. Hyperkalemia is an uncommon side effect, but serum potassium should be checked 1 month after beginning therapy or after dosage increases. Spironolactone should be avoided or used cautiously in women with kidney disease or who are taking an ACE inhibitor or ARB. Spironolactone should not be given with an oral contraceptive containing drospirenone because the progestin has an anti-mineralocorticoid effect that predisposes to hyperkalemia. Trimethoprim-sulfamethoxazole should not be taken along with high-dose spironolactone. Trimethoprim has potassium-sparing diuretic effects and combining it with spironolactone increases the risk of severe hyperkalemia and sudden death. Side effects of spironolactone include breast tenderness, menstrual irregularity, headaches, nausea, and fatigue, which may improve with continued treatment or dose reduction; paradoxical scalp hair loss has been reported at higher doses.

Flutamide and bicalutamide inhibit testosterone binding to androgen receptors and also suppress serum testosterone. These drugs can rarely cause severe hepatotoxicity and exposure during pregnancy causes fetal malformations. Therefore, the use of these drugs for hirsutism is discouraged. They should only be used as a last resort for women with severe hirsutism/virilization and only with very close monitoring for hepatic toxicity and strict contraceptive precautions due to risks of fetal malformations. Flutamide is given orally in a dosage of 250 mg twice daily for the first year and then 125-250 mg/day for maintenance. Flutamide decreases cortisol renal clearance and corticosteroid replacement doses (eg, in congenital adrenal hyperplasia) should be reduced when flutamide is added. Bicalutamide is given in a dosage of 50 mg once daily.

Finasteride inhibits 5-alpha-reductase, the enzyme that converts testosterone to active dihydrotestosterone in the skin. Due to inconsistent reduction in hirsutism and androgenic alopecia and risk of pseudohermaphroditism in male infants if mistakenly taken during pregnancy, finasteride for hirsutism is strongly discouraged for women who can potentially become pregnant.

Metformin alone is ineffective in improving hirsutism but can enhance the anti-hirsutism effect of spironolactone. Start metformin at a dose of 500 mg/day with breakfast for 1 week, then increased to 500 mg with breakfast and dinner. If this dose is clinically insufficient but tolerated, the dose may be increased to 850-1000 mg twice daily with meals. The most common side effects are dose-related GI upset and diarrhea or constipation. Metformin appears to be nonteratogenic. Although metformin reduces insulin resistance, it does not cause hypoglycemia in patients without diabetes. Metformin is contraindicated in severe kidney or liver disease. GLP-1 agonist therapy reduced weight and serum testosterone levels in women with PCOS in one short-term study. However, an effect on hirsutism has not been demonstrated clinically.

Simvastatin and atorvastatin can reduce hirsutism in women with PCOS. When given to women taking an oral contraceptive, these statins lead to a greater decrease in hirsutism and serum free testosterone than an oral contraceptive alone.

Women with classical congenital adrenal hyperplasia (21-hydroxylase deficiency) with hirsutism and adrenal insufficiency require glucocorticoid and mineralocorticoid replacement. However, women with partial "late-onset" 21-hydroxylase deficiency are not cortisol deficient and do not require glucocorticoid replacement. Glucocorticoids are ineffective in reducing hirsutism in these women. However, replacement doses of glucocorticoids (prednisone, methylprednisolone) may be indicated to normalize menses and for ovulation induction. However, long-term administration of supraphysiologic doses of glucocorticoids should be avoided. Adrenal steroidogenesis inhibitors, such as nevanimibe, are under investigation for women with virilization due to congenital adrenal hyperplasia.

GnRH agonist therapy has been successful in treating postmenopausal women with severe ovarian hyperandrogenism when laparoscopic oophorectomy is contraindicated or declined by the patient.

C. Surgery

Androgenizing tumors of the adrenal or ovary are resected laparoscopically. Postmenopausal women with severe hyperandrogenism should undergo laparoscopic bilateral oophorectomy (if CT scan of the adrenals and ovaries is normal), since small hilar cell tumors of the ovary may not be visible on scans. Women with classic salt-wasting congenital adrenal hyperplasia and infertility or treatment-resistant hyperandrogenism may be treated with laparoscopic bilateral adrenalectomy.